Signal transduction from N-cadherin increases Bcl-2. Regulation of the phosphatidylinositol 3-kinase/Akt pathway by homophilic adhesion and actin cytoskeletal organization

• Published in: The Journal of biological chemistry Vol. 277; no. 36; pp. 32905 - 32914
• Main Authors: Tran, Nhan L, Adams, Deanna G, Vaillancourt, Richard R, Heimark, Ronald L
• Format: Journal Article
• Language: English
• Published: United States 06.09.2002
• Subjects: Actin Cytoskeleton - metabolism; Actins - metabolism; Apoptosis; bcl-2-Associated X Protein; Cadherins - metabolism; Calcium - metabolism; Cell Adhesion; Cell Survival; DNA, Complementary - metabolism; Glutathione Transferase - metabolism; Humans; Immunoblotting; Microscopy, Fluorescence; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Plasmids - metabolism; Precipitin Tests; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Signal Transduction; Time Factors; Transfection; Tumor Cells, Cultured; Vinculin - metabolism
• DOI: 10.1074/jbc.M200300200
• ISSN: 0021-9258

Associated with the metastatic progression of epithelial tumors is the dynamic regulation of cadherins. Whereas E-cadherin is expressed in most epithelium and carcinomas, recent studies suggest that the up-regulation of other cadherin subtypes in carcinomas, such as N-cadherin, may function in cancer progression. We demonstrate that a signal transduction cascade links the N-cadherin.catenin adhesion complex to up-regulation of the anti-apoptotic protein Bcl-2. In suspension, aggregates of DU-145 cells, an E-cadherin expressing human prostate carcinoma line, survive loss of integrin-dependent adhesion by a different anti-apoptotic signaling pathway than the N-cadherin expressing lines PC3 and PC3N. N-cadherin intercellular adhesion mediates a 3.5-fold increase in Bcl-2 protein expression, whereas the level of the proapoptotic protein Bax remains constant. Only N-cadherin ligation in PC3 cells, which express both N-cadherin and E-cadherin, is sufficient to induce activation of Akt/protein kinase B. N-cadherin homophilic ligation initiates phosphatidylinositol 3-kinase-dependent activation of Akt resulting in Akt phosphorylation of Bad on serine 136. Following N-cadherin homophilic adhesion phosphatidylinositol 3-kinase was identified in immunoprecipitates of the N-cadherin.catenin complex. The recruitment of phosphatidylinositol 3-kinase to the adhesion complex is dependent on ligation of N-cadherin and an organized actin cytoskeleton because cytochalasin D blocks the recruitment. We propose that N-cadherin homophilic adhesion can initiate anti-apoptotic signaling, which enhances the Akt cell survival pathway in metastatic cancer.